Advances in Cancer Biology Research
Over the past year, research projects funded by the Division of Cancer Biology (DCB) have led to many new discoveries and advances in basic cancer research that continue to lay the groundwork for future clinical breakthroughs and cancer prevention strategies. Below are examples of important cancer biology findings.
Cancer Cell Biology
Martinez-Ordoñez et al. found that hyaluronan promotes mesenchymal colorectal cancer progression and that targeting this molecule suppresses tumor growth in experimental models. In describing the work, Dr. Jorge Moscat (principal investigator of the study) said, "We have unraveled one of the critical mechanisms driving this aggressive type of colorectal cancer, and we are proposing a potential therapy for patients who currently have few options.”
Nwosu et al. showed that pancreatic cancer can readily turn to an alternate source of energy to survive when its primary source, glucose (a sugar molecule), is in short supply. They found that pancreatic cancer cells overcome glucose deprivation by using an alternative source of fuel, specifically a molecule called uridine.
Using screening approaches and experimental models, Weiss-Sadan et al. revealed that reductive stress is a metabolic vulnerability in NRF2-activated lung cancers. They showed how over-activation of NRF-2 antioxidant signaling leads to a reduced cellular state, which creates synthetic lethal opportunities within a subset of lung cancers.
Additional research in this area is supported by the DCB Cancer Cell Biology Branch.
Cancer Immunology, Hematology, and Etiology
Using preclinical models of melanoma, Lester et al. showed that L-fucose (a dietary plant sugar found in seaweeds) promotes anti-tumor immunity and improves the efficacy of immunotherapy. They also found that higher levels of L-fucose in clinical samples from skin cancer patients are associated with less aggressive disease and better responses to immune checkpoint blockade.
Broussard et al. discovered that barrier-to-autointegration factor 1 (BAF1) is necessary for the reactivation of oncogenic gammaherpesviruses (e.g., Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus).
Mandula et al. showed that targeting PERK promotes the activation of anti-tumor immunity and suppresses melanoma growth in preclinical models. The findings reveal that PERK is a potential therapeutic target in skin cancer that could be leveraged to enhance immunotherapy.
Additional research in this area is supported by the DCB Cancer Immunology, Hematology, and Etiology Branch.
DNA and Chromosome Aberrations
Using functional genomics screens, phosphoproteomics, and experimental models, Dhital et al. identified MASTL kinase as a therapeutic vulnerability in metastatic chemotherapy-resistant prostate cancer. The findings showed that chromosomal instability tolerance mechanisms are a treatment target in this lethal type of cancer.
Girish et al. found that cancer cells with extra chromosomes (i.e., aneuploidy) depend on those chromosomes for tumor growth. They further showed that eliminating the extra chromosomes prevents cells from forming tumors in preclinical models.
Brambati et al. showed that RHINO promotes DNA repair by microhomology-mediated end joining during mitosis (i.e., cell division). The findings offer insights into the synthetic lethal relationship between POLQ, BRCA1, and BRAC2, as well as the synergistic effect of PARP inhibitors.
Additional research in this area is supported by the DCB DNA and Chromosome Aberrations Branch.
Biophysics, Bioengineering, and Computational Sciences
Gourisankar et al. revealed a new approach for rewiring cancer drivers to activate cell death (i.e., make cancer cells self-destruct).
Tiny Implanted Devices Give Insights for Treating Brain Tumors
Scientists developed and tested drug releasing microdevices for assessing how well various brain tumor treatments might work for each patient.
Pedram et al. bioengineered enzyme-based scissors that cut mucins off cancer cells, removing their protection from the immune system. This approach promotes cell death and inhibits tumor growth in preclinical models.
Hu et al. developed a computational pipeline using ChatGPT-4 to label gene sets with names that summarize their functions based on scientific literature. The work shows that Large Language Models provide a new and powerful tool for functional genomics and new hypothesis generation.
Additional research in this area is supported by the DCB Biophysics, Bioengineering, and Computational Sciences Branch (BBCSB).
Tumor Biology and Microenvironment
Du et al. found that WNT signaling in the tumor microenvironment promotes immunosuppression in pancreatic cancer. They further showed that a clinically available inhibitor of WNT signaling enhances T cell responses and sensitizes tumors to immunotherapy in preclinical models.
Faget et al. showed that p38MAPKα inhibition (p38i) suppresses breast cancer growth by reprogramming the metastatic tumor microenvironment. They also found that p38i in combination with an immunotherapy drug synergistically reduces metastatic growth and increases overall survival in preclinical models.
A Gastric Cancer Microenvironment Atlas Reveals Insights into Tumor Biology and Therapeutic Targets
Researchers revealed the progression of gastric adenocarcinoma through an analysis of single cells and the tumor microenvironment.
Mahadevan et al. found that MRTX1133 (a small molecule inhibitor targeting oncogenic KRAS) enhances T cell responses and suppresses tumor growth in preclinical models of pancreatic cancer. They also showed that immune checkpoint blockade synergizes with MRTX1133 treatment.
Additional research in this area is supported by the DCB Tumor Biology and Microenvironment Branch.
Tumor Metastasis
Using experimental models of breast cancer, Duran et al. revealed a mechanism that promotes macrophage mediated MenaINV expression, which is needed for cancer cell dissemination. They further showed that targeting this mechanism decreases MenaINV expression in the primary tumor and decreases metastasis in preclinical models.
Kim et al. found that cell competition within a primary tumor shapes metastatic latency and relapse. They also showed that altering cell competition dynamics attenuates metastases in preclinical models.
Using experimental approaches, Lei et al. showed that tumor cell plasticity and immune tolerance promote breast cancer metastasis to lymph nodes. When describing the research, Dr. Ping Lei (first author of the study) said, “Our findings have significant implications for developing effective treatments to target lymph node metastases, prevent cancer spread to other organs, and restore anti-tumor immunity in the tumor-draining lymph nodes."
Additional research in this area is supported by the DCB Tumor Metastasis Branch.
DCB Research Programs
Steele et al. with the Metastasis Research Network (MetNet) showed that lymphatic vessels control T cell escape from tumors via CXCL12. They further found that inhibition of the CXCL12 pathway enhances anti-tumor immunity and responses to immunotherapy in preclinical models of melanoma.
Su, Yang, et al. with the Pancreatic Ductal Adenocarcinoma (PDAC) Stromal Reprogramming Consortium (PSRC) showed that different collagen species have opposing effects on tumor progression. They found that while cleaved collagen I activates the discoidin domain receptor 1 (DDR1) and promotes pancreatic cancer development, intact collagen I drives DDR1 degradation and blocks pro-tumorigenic signaling.
Epigenetic Plasticity Cooperates with Cell-Cell Interactions to Drive Pancreatic Cancer Development
Scientists identified mechanisms involving the expansion of cell communication that direct pancreatic tumorigenesis using systems biology approaches.
Kiemen et al. with the Cellular Cancer Biology Imaging Research (CCBIR) Program and Physical Sciences – Oncology Network (PS-ON) developed CODA, a method to reconstruct large tissues at subcellular resolution using tissue sections. They further showed how this technique enables studies of tissue microarchitecture and cancer progression.
DCB research programs supported these studies, as well as foster emerging areas and model development in cancer biology.